What are the remain challenges and expected changes in the future management of type 2 diabetes?

Interview with H. E. Lebovitz,USA

While there are now many classes of oral and injectable therapies for the management of type 2 diabetes, ideal glycemic control, elimination of chronic diabetic complications, and prevention of type 2 diabetes remain elusive. The primary reasons for the inability of current treatments to achieve these goals are the progressive loss of β cell function with time, the significant side effects associated with our current therapies, the inability of current strategies to control body weight and decrease the prevalence of the metabolic syndrome, and the lack of patient compliance to current therapeutic programs for type 2 diabetes management. The introduction of therapies that are weight neutral or promote weight loss and do not cause hypoglycemia has been a significant advance over the last decade or two. However, there are continuing challenges and the future of type 2 diabetes management will focus on β cell replenishment, the development of delivery platforms that will achieve near-total compliance, the development of new treatment paradigms for type 2 diabetes that will correct abnormal physiology and have minimal side effects, and an effective practical program to treat obesity.

How does type 2 diabetes treatment today differ from that of 20 years ago?

Type 2 diabetes mellitus (T2DM) treatment has evolved in the last twenty years. The results of the DCCT trial (Diabetes Control and Complications Trial) in 1993 and the UKPDS study (United Kingdom Prospective Diabetes Study) in 1998 established the relationship between glycemic control and microvascular complications of diabetes mellitus, and set the goal for glycemic control to be ≤7.0%. This was achieved with sulfonylurea drugs and/or metformin or subcutaneous regular or intermediate-acting insulin injections. During the last twenty years, new classes of drugs that utilize different and, in some instances, more physiological mechanisms of action have emerged to achieve glycemic control.1 The most widely used of these new drugs are the thiazolidinediones, which reduce insulin resistance, dipeptidyl peptidase-4 (DPP-4) inhibitors, and GLP-1 (glucagon-like peptide- 1) receptor agonists, which increase incretin effects, sodium-glucose transporter 2 (SGLT-2) inhibitors, which block the renal tubular reabsorption of glucose, and a-glucosidase inhibitors, which inhibit the intestinal absorption of complex carbohydrates. These new classes of antihyperglycemic agents provide additionalmeans of obtaining target glycemic control while, at the same time, minimizing hypoglycemia, eliminating weight gain or, in some instances, even promoting weight loss and reducing cardiovascular risk factors. Cardiovascular outcomes are being documented with all of the newer treatment modalities. Several of these studies have been linked with reductions in hospitalizations for congestive heart failure and cardiovascular death (empagliflozin)2 and a reduction in a composite of major adverse cardiovascular events (liraglutide).3 These newer agents allow more specific targeting of fasting and postprandial hyperglycemia. Newer “rapid acting” prandial and basal insulins increase the effectiveness of insulin therapy. A major change in therapy is the use of combination drug therapy for glycemic control and to reduce inertia in implementing progression of therapy in patients failing target glycemic control.

What are the current challenges we face in treating and managing type 2 diabetes?

Major challenges in managing T2DM are: (i) patient health care beliefs and compliance; (ii) increasing incidence and severity of obesity; (iii) physician confusion about the relationship between hyperglycemia and macrovascular complications; (iv) inability to identify which patients with T2DM will have the best response to each particular class of antihyperglycemic agents.

T2DM is a chronic disease requiring lifelong treatment and follow-up. For a patient to follow a treatment program, he/she must believe that the program will achieve beneficial results and that the potential results are greater than the difficulties or side effects of the treatment. Many patients with T2DM fail to identify the serious nature of their disease until they have significant clinical symptoms or signs of the illness. When treatment ameliorates the symptoms and lessens the signs, the perception is that the diabetes is no longer a meaningful threat. Effective public awareness and educational programs are the cornerstone of modifying health care beliefs for patients with prediabetes and diabetes.

In a recent study of 75 589 insured patients treated by 1217 prescribers in a community-based e-prescribing initiative, 31% of new prescriptions for diabetes medications were never filled.4 Once diabetic medicines are started, compliance for oral medications (sulfonylureas, DPP-4 inhibitors, thiazolidinediones) at 1 year was 42% and 34.6% at 2 years.5 Compliance at 1 year with injectable GLP-1 receptor agonists was 34%.6 Increasing compliance is being approached in several ways: by increasing patient education about the value of good metabolic control and how medications improve this control; by providing drugs in systems that can deliver 6 to 12 months of treatment; and by creating treatments that are effective and have minimal side effects. The increasing prevalence and severity of obesity is the major cause of the increase in prevalence of T2DM. Lifestyle and pharmacological interventions have failed to reduce obesity in the long term. Pharmacological treatments generally show a mean decrease in body weight of ≤5%, require continuous therapy, and are associated with significant side effects. Their impact on glycemic control and chronic complications is minimal. Metabolic surgery is highly effective in reducing body weight and improving HbA1c, but the longterm effects on diabetic complications are not well documented and chronic complications of the surgery and its subsequent nutritional deficiencies restrict its usefulness.

Many health care providers interpret the current cardiovascular studies as showing that glycemic control is not meaningful in reducing cardiovascular events, and focus on blood pressure and lipid management while minimizing glycemic control. Glycemic control is not effective in reducing macrovascular events in patients who already have significant macrovascular disease, but it does reduce long-term macrovascular events if initiated before there are significant structural changes in the large blood vessels. The benefits of glycemic control in reducing microvascular disease are unquestionable.

It is obvious that T2DM is a heterogeneous group of phenotypically similar but genetically disparate illnesses. Patient responses to glycemic control therapies vary dramatically. Primary failure rates are 25% for sulfonylureas and 25% for metformin. Some genotypes of TCF-7L are more responsive to sulfonylurea while others are not. Genetic variants in either subunit of the ATP-dependent potassium channel can cause either T2DM or severe intractable hypoglycemia. The number of known monogenetic forms of diabetes has risen from 5 to 13. Japanese patients with T2DM appear to be more responsive to treatment with DPP-4 inhibitors than Caucasians.7 In the future, we will use pharmacogenetics to identify the pharmacological agents that will give the best glycemic control with the fewest side effects for individual patients.

In your opinion, what have been the most important advances in type 2 diabetes over the past few decades?

The most important advances in T2DM over the past two decades have been the definition of the metabolic syndrome, the discovery of physiological mechanisms underlying β cell function, the physiology of the incretin system, and the development of new treatments for T2DM based on our understanding of its pathophysiology.

The metabolic syndrome is a series of metabolic abnormalities, the totality of which are associated with a 2- to 3-fold increased risk of cardiovascular disease and a 6-fold increased risk of developing T2DM. Whether specifically designated or not, central adiposity with insulin resistance is the driving force for the metabolic syndrome. Insulin resistance forces the β cell to compensate with increased insulin secretion andthe inability of the genetically abnormal β cell to adequately compensate results in relative insulin deficiency and T2DM. This phenomenon explains much of the recent T2DM epidemic. The metabolic abnormalities related to the increase in visceral fat are explanations for the increase in cardiovascular events and non-alcoholic steatohepatitis.

Increased knowledge of β cell physiology has contributed significantly to understanding the pathophysiology of hypoglycemic and hyperglycemic states as well as the mechanism of action of insulin secretagogues. The identification of the ATP-dependent potassium channel in the β cell plasma membrane and its two subunits, Kir6.2 and SUR1, defined the mechanism of action of sulfonylurea drugs, and genetic polymorphisms explained both neonatal diabetes and neonatal idiopathic hypoglycemia. The identification of the GLP-1 receptor linked to adenylate cyclase explained the mechanism by which GLP-1 and its analogues potentiate glucose-stimulated insulin secretion.

The discovery of incretins has led to identification of the role of the gastrointestinal tract in the physiological regulation of nutrient metabolism. Deficient incretin action contributes to the pathophysiology of T2DM. The development of DPP-4 inhibitors and GLP-1 receptor agonists for the treatment of T2DM was the outgrowth of uncovering the existence and function of incretin hormones.

Understanding the role of the kidney in reabsorption of glucose in physiological and pathophysiological states led to the development of SGLT-2 inhibitors.

What are the most important risk factors favoring the occurrence of type 2 diabetes likely to be in the future and how can we mitigate their impact now?

The increase in T2DM is pandemic; it started in the 1980s and parallels the increase in obesity. The major identifiable risk factors are those associated with the metabolic syndrome. Of those, an increase in visceral and hepatic fat leading to ectopic fat deposits in tissues, such as muscle, heart, and β cells leads to insulin resistance and insulin secretory deficiency. Preventing obesity and the metabolic syndrome will decrease the future occurrence of T2DM. Appropriate nutrition and modest exercise starting from childhood and adolescence have the greatest likelihood of preventing obesity and the metabolic syndrome. It is quite difficult to treat established obesity. At the present time, the numerous dietary interventions and pharmacological treatments have not resulted in significant long-term positive results either in weight loss or the prevention of T2DM. Bariatric surgery accompanied by body weight losses of ≥20% has been shown to dramatically reduce the occurrence of future T2DM.

It is likely that processed foods, stress, and other environmental factors contribute to the increased occurrence of T2DM, but concrete data concerning the magnitude of such effects are not available.

How important is our understanding of the pathogenesis of type 2 diabetes in the improvement of management?

In the past, new pharmacological therapies for T2DM (metformin, sulfonylureas, thiazolidinediones) were discovered serendipitously or through drug screening procedures. Recently, new treatments have been engineered based upon our knowledge of the pathophysiology of T2DM. α-Glucosidase inhibitors were designed to specifically block postprandial carbohydrate absorption and lower postprandial glycemic excursions. The discovery of the incretin effect led to the isolation and structure of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1.

Recognition of the role of incretin hormones in correcting the pathophysiology of T2DM led to the development of molecules that bypassed the proteolytic actions of the ubiquitous DPP-4, which rapidly cleaves endogenous GLP-1 and GIP. One class of molecules blocks the activity of DPP-4 (DPP-4 inhibitors) and increases postprandial plasma GLP-1 and GIP levels 2- to 3-fold. There are now more than 8 such drugs in clinical use or development for the treatment of T2DM. GLP-1 receptor agonists are the other class of incretin-active molecules. These drugs retain GLP-1 activity, but have modifications in their structure that make them resistant to cleavage by DPP-4. There are 6 such drugs in clinical use and many more in development.

The SGLT-2 inhibitors are another class of drugs that were specifically engineered based on the pathophysiology of T2DM. These molecules inhibit SGLT-2, which is in the renal proximal tubule and is responsible for the reabsorption of 90% of the filtered glucose. Inhibition of SGLT-2 results in urinary glucose excretion at plasma glucose levels of ≥100 mg/dL rather than ≥240 mg/dL as occurs in patients with T2DM. The block of renal reabsorption of glucose results in decreases in plasma glucose and HbA1c.

Almost all new treatments in development now are based upon our recent knowledge of the pathophysiology of T2DM.

What advances in public health sciences will help counter the increasing toll that type 2 diabetes inflicts on society?

Countering the increasing toll that T2DM inflicts on society requires decreasing the incidence of new cases of diabetes, improving the care of those with diabetes to prevent the complications of diabetes, and doing both at costs that societies will be able to afford.

The diabetes problem is pandemic. There are currently 400 million persons with diabetes and the number is expected to increase by 50% by 2030. Diabetes is the leading cause of visual loss in adults under 65 years of age, is responsible for 50% of patients developing end stage renal disease, is an underlying cause of 60% of patients presenting with coronary heart disease, and is the leading cause of nontraumatic lower extremity amputations. The cost of diabetes to society includes direct costs for treating the metabolic abnormalities (hyperglycemia, hypertension, and dyslipidemia), the direct costs of managing the microvascular and macrovascular complications, and many indirect costs, such as lost wages and payments for assisted care.8

Increasing the use of expensive medicines and procedures in such a large and rapidly increasing population is not possible. Ultimately, changes in lifestyle starting from childhood will be absolutely necessary to curb the development of the metabolic syndrome and T2DM. This will require extensive changes in public policy with the introduction of major public education programs and with the use of rewards and penalties to obtain compliance. In those who develop T2DM and cannot be adequately treated by lifestyle measures, reliance on targeted treatments that are the most cost effective will need to be made widely available.

What areas of research should we focus on to improve the future management of type 2 diabetes?

Two areas of research are likely to provide information that will improve the future management of T2DM. The first area is to define the basic mechanisms responsible for the development of T2DM. This includes identifying the constellations of genes responsible for the pathogenesis of T2DM in individuals. T2DM, as we currently define it, is a series of diseases that phenotypically are similar, but probably have significant genetic differences. Identification of differences in genetic patterns may lead to a better understanding of the clinical course of individual patients with T2DM and to target their therapy to abnormalities that are specific to their genotypes. Fundamental to understanding and treating T2DM is unraveling the mechanisms responsible for the loss of β cell mass and function. Treating these abnormalities is the approach to treating prediabetes and stopping the progression of T2DM. Another approach to the cell abnormalities is the development of physiologically normal β cells from stem cells.9 This would provide a pool of β cells for transplantation into patients with both T1DM and T2DM.

The second area is to define the biochemical mechanism by which chronic hyperglycemia causes tissue injury and develop treatments that block the detrimental tissue effects of hyperglycemia. This area of research was very active 20 years ago, but it has been virtually abandoned. Such agents, if effective, would greatly simplify the complex methods used today for intensive glycemic control.

How do you imagine that type 2 diabetes treatment in 20 years’ time might differ from that of today?

T2DM management 20 years from now will be more personalized, more focused on treatments that correct altered physiology rather than pharmacologically altering function, concerned with side effect profiles as much as the magnitude of A1C lowering, and delivered with platforms that provide high compliance. Genetic profiling will identify a number of different subtypes of T2DM, and these subtypes will respond differently to available treatment paradigms. The prescribed therapy for a patient will be determined by the subtype of their T2DM and their specific pharmacogenetic pathways for the potential therapeutic treatments. They will be treated with the most effective treatment that will cause the least significant side effects. A current example of differential responses to treatments was provided by meta-analyses suggesting that Asian T2DM has a greater glycemic response to incretin based therapies than Caucasian T2DM. Pharmacogenetic profiling can help identify patients at risk for serious side effects to a drug or class of drugs and thus eliminate them as potential treatments.

Treatments that correct the abnormalities that cause the various forms of T2DM will do so by correcting the abnormal physiology. Increasing incretin activity will be done by stimulating endogenous incretin hormone secretions rather than injecting incretin hormone analogs. Neural centers that regulate energy balance and metabolism will be activated and corrected by exogenous nutrient-mediated gastric or intestinal electrical stimulatory devices. These devices recognize food and nutrient intake, generate stimulatory signals to the organ, which then activates the gut-brain-liver and islet neural circuits that regulates food intake and nutrient metabolism. Correcting the metabolic abnormalities of T2DM by modifying the normal physiological pathways can provide the best treatments with minimal or no side effects.

The major cause of treatment failure in T2DM is a lack of compliance. This can be solved by developing treatment platforms that minimize compliance errors. The delivery of medications by osmotic minipumps inserted into the abdominal subcutaneous fat can provide 6 to 12 months of continuous drug administration (see the Focus article: New Technology For Improving Patient Care in this issue). Such a system delivering exenatide is in clinical trials now. Implantable gastric electric stimulatory devices that are automatically activated by detection of food intake and can treat T2DM for as long as 3 to 5 years are currently completing clinical trials.10 Devices and delivery systems such as these will be used extensively in 20 years and compliance issues will be minimized. Finally, b cell replacement therapy is likely to be available in 20 years. ■

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Keywords: compliance management; electrical stimulation; genetic profiling; metabolic syndrome; new therapy; osmotic pump; pharmacogenetics; physiological regulation